Superantigens for the receptors of B lymphocytes that have properties akin to known superantigens for T cells have only recently been identified. The current ISA program is designed to enhance the research program of the candidate, to enable more in depth studies of a bacterial membrane protein, that we discovered has the structural and functional properties of a B-cell superantigen. We have demonstrated that Staphylococcal protein A (SpA) has sites that enable binding by >15% of human B cells, and most (and perhaps all) functional germline gene segments from the VH3 family can encode for Fab-mediated binding of SpA. Our recent observations also provide the first experimental evidence that in vivo exposure to SpA can result in dramatic global changes in the composition of the B-cell repertoire. To extend our investigations of this model B-cell superantigen, we propose to; i) perform site-specific mutagenesis studies of antibody V genes with expression in bacterial and mammalian cells to evaluate potential SpA contact sites at the molecular level, ii) genetically engineer new forms of SpA with properties that are optimized for the in vivo stimulation of B-cell subpopulations, iii) use murine immunization models to investigate the in vivo capacity for SpA to selectively influence VH-based clonal expansion, deletion and!or anergy, and iv) investigate the capacity of SpA to interact with pre-B cells and B-cell surrogate Ag receptors in vitro. The current program is designed to foster close collaborative efforts with UCSD and non-UCSD researchers of diverse clinical and scientific training, in a multidisciplinary approach to the evaluation of the capacity of superantigens to influence the acquisition of the B-cell repertoire. The candidate will direct these studies from space provided by an organized research unit created to facilitate interdepartmental interactions. The longterm goal of these studies is to demonstrate the feasibility of using B-cell superantigens in clinically relevant settings that include the selective expansion of defined B-cell precursors for transplantation, or the deletion of neoplastic or disease-associated autoimmune B-cell clones. New approaches for the augmentation of protective immune responses to infection will also be considered.